Fig. 40.5 ). Vitamin D2 (ergocalciferol) is produced in plants. Vitamin D3 and to a lesser extent vitamin D2 are absorbed from the diet and are equally effective after conversion to active hydroxylated forms. The balance between UVB-dependent endogenously synthesized vitamin D3 and absorption of the dietary forms of vitamin D becomes important in certain situations. Individuals with higher melanin content in skin who live at higher latitudes convert less 7-dehydrocholesterol to vitamin D3 and thus are more dependent on vitamin supplements or dietary sources of vitamin D (natural or fortified, e.g., milk). Institutionalized elderly patients who stay indoors and avoid dairy products are particularly at risk for development of vitamin D deficiency.
Vitamin D is transported in blood from the skin to the liver. Dietary vitamin D reaches the liver directly via transport in the portal circulation and indirectly via chylomicrons (see
Fig. 40.6 ). In the liver, vitamin D is hydroxylated at the 25-carbon position to yield 25-hydroxyvitamin D. The hepatic 25-hydroxylase is constitutively expressed and unregulated, so circulating levels of 25-hydroxyvitamin D reflect the amount of precursor available for 25-hydroxylation. For this reason, and because of its relatively long half-life in the circulation (2–3 weeks), measurement of 25-hydroxyvitamin D levels is used to assess vitamin D status.
25-Hydroxyvitamin D undergoes further hydroxylation in the proximal tubule of the kidney (see
Figs.
40.5 40.6).
Hydroxylation at the 1α position generates 1,25-dihydroxyvitamin D, the most active form of vitamin D. Hydroxylation at the 24 position generates 24,25-dihydroxyvitamin D, which does not play a major biological role and serves as an inactivation pathway.
Renal 1α-hydroxylase is tightly regulated by a number of factors (
Fig. 40.7). PTH and hypophosphatemia are the primary inducers of 1α-hydroxylase activity, resulting in 25(OH)D3 1˜-hydroxylase 1,25(OH)2D3 25(OH)D3 CYP27B1 FGFRKIotho •Fig. 40.7 Regulationof1α-hydroxylasegene(CYP27B1) expressionintheproximaltubule,showingstimulationbyPTHandinhibitionbyFGF23and1,25-dihydroxyvitaminD.Hypophosphatemiaprobablystimulates1α-hydroxylasebyreducingFGF23levelsatleastinpart.
increased levels of 1,25-dihydroxyvitamin D. Conversely, [Ca++] and 1,25-dihydroxyvitamin D, the enzyme product, inhibit it. Fibroblast growth factor (FGF)23, a major regulator of Pi metabolism (see later), also represses 1α-hydroxylase activity; a reduction of FGF23 levels likely mediates the effect of hypophosphatemia on 1,25-dihydroxyvitamin D production at least in part.